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Preliminary results of serum androgen level testing in men with rheumatoid arthritis.

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Preliminary results of serum androgen level testing in
men with rheumatoid arthritis
To the Editor:
In recent years, there has been considerable evidence substantiating the ability of sex hormones to modulate
the immune response (I). Clinical investigations have examined the possible pathogenetic role of sex hormones in
rheumatoid arthritis (RA) (2), and have attempted to correlate serum hormone levels with the clinical characteristics of
patients with systemic lupus erythematosus (SLE) and other
autoimmune disorders (3). Recently, Dougados et al (4)
examined plasma levels of androgens in female patients with
RA, and noted no substantially decreased levels as compared with a control population.
In light of these data, we evaluated the serum levels
of androgens in male RA patients. Serum concentrations of
testosterone (T), ACandrostenedione (A), dihydrotestosterone (DHT), dihydroepiandrosterone-sulfate(DHEAS), and
cortisol (F) were determined in 7 men (mean age 65 t 6
years) with classic or definite RA, as defined by American
Rheumatism Association criteria (5). Results were compared
with those of a control group consisting of 6 men (mean age
60 11 years) with secondary osteoarthritis.
At the time of the study, all 13 patients were being
treated with nonsteroidal antiinflammatory drugs exclusively. None of the patients had received oral or intraarticular
corticosteroids for at least 3 months before the study; no
patients were administered exogenous estrogens or androgens.
Early morning (9:OO-11 :OO)blood samples were collected from all 13 patients and were stored at -20°C until the
hormone assays were performed. T , A, and DHT were
isolated from sera by diethylether extraction and celite
column chromatography (6).DHEAS was directly measured
from diluted serum samples. Assays of T, A, and DHEAS
levels were performed by radioimmunoassay (6); F was
directly determined by solid-phase radioimmunoassay (6).
Results obtained are reported in Table 1.
Our data indicate that serum androgen concentrations
are lower in male RA patients when compared with sex- and
age-matched control subjects.*In particular, we observed a
significant decrease in levels of T and DHEAS, suggesting
impaired gonadal production of androgens.
Recent evidence suggests that androgens and estrogens have opposing effects on the immune response (7). This
has served to explain, in part, the characteristic excess of
females with autoimmune disorders. Recent clinical observations concerning the reduction of RA symptoms in patients during the postovulatory phase of the menstrual cycle,
and the decrease of circulating immune complexes during
pregnancy in RA patients, stress the significance of sex
hormones in the modulation of RA symptoms (8).
In particular, hormonal studies in both male and
female patients with SLE have demonstrated altered estrogen metabolism (9). Furthermore, exacerbations of SLE
have been noted in female patients taking estrogen-containing oral contraceptive pills, and elevated estradiol :testosterone ratios have been documented in male patients with SLE.
On the other hand, androgens have been shown to
have protective effects in SLE. This is best illustrated in the
murine lupus models, in which androgens can correct a
number of the abnormal immunologic parameters: androgens will decrease autoantibody production and immune
complex nephritis, improve macrophage activity, and reverse deficiency of interleukin-2 (T cell growth factor) (10).
Although our study was performed on a very limited
number of patients, our data are in accord with previous
reports on the subject. We suggest that the combination of
altered estrogen metabolism and reduced plasma androgens
provides a favorable setting for the development of autoimmune disorders. The presence of decreased levels of androgens in RA patients is consistent with their immune suppressive activity.
Maurizio Cutolo, MD
Enrico Balleari, MD
Silvano Accardo, MD
Elpis Samanta, MD
Marco A. Cimmino, MD
Rheumatological Center
Massimo Giusti, MD
Mario Monachesi, MD
Agnese Lomeo, MD
Cattedra di Endocrinologia
Genoa University
Genoa, Italy
Table 1. Androgen concentration in male patients with RA and control subjects (mean
RA patients
(n = 7)
Control subjects
(n = 6)
(nd100 ml)
* 42.22
(ng/100 ml)
99.98 2 63.67
4.79 f 2.47
146.95 2 57.52
* RA = rheumatoid arthritis; T = testosterone; A = A4-androstenedione; DHT
tosterone; DHEAS = dihydroepiandrosterone-sulfate;F = cortisol.
t P < 0.05.
(pg/100 ml)t
64 ? 61.98
124.29 f 38.72
1 . Rdubinian J, Talal N , Siiteri PK, Sadakian JA: Sex hormone
modulation of autoimmunity in N%B/NZW mice. Arthritis
Rheum 22: 1162-1 169, 1979
2. Pope RM, Yosminoya S, Rustein J , Persellin RH: Effect of
pregnancy on immune complexes and rheumatoid factors in
patients with rheumatoid arthritis. Am J Med 74:973-979, 1983
3. Stahl NI, Decker JL: Androgenic status of males with systemic
lupus erythematosus. Arthritis Rheum 21565-667, 1978
4. Dougados M, Nahoul K, Benhamou L, Amor B: Androgen
plasma levels in female rheumatoid arthritis patients (letter).
Arthritis Rheum 26:935-936, 1983
5. Ropes MW, Bednett GA, Cobb S , Jacox k, Jessar RA: 1958
revision of diagnostic criteria for rheumatoid arthritis. Bull
Rheum Dis 9: 175-176, 1958
6. Giusti M, Marugo M, Mazzocchi G, Bernasconi D, Bessarione
D, Magistro G, Mignone D, Giordano G: An assessment of
hirsutism by the simultaneous determination of four plasma
androgens, Androgenization in Women. Edited by G Molinatti,
L Martini, VHT James. New York, Raven Press, 1983, pp 147153
7. Talal N: Sex steroid hormones and systemic lupus erythematosus. Arthritis Rheum 24: 1054-1056, 1981
8. Latman NS: Relation of menstrual cycle phase to symptoms of
rheumatoid arthritis. Am J Med 74:957-960, 1983
9. Lahita RG, Bradlow HL, Kunkel MG, Fishman J: Increased
16a-hydroxylation of estradiol in systemic lupus erythematosus.
J Clin Endocrinol Metab 53:174-178, 1981
10. Jungers P, Dougados M, Pelissier C, Kuttenn F, Tron F,
Lesavre P, Bach JF: Influence of oral contraceptive therapy on
the activity of systemic lupus erythematosus. Arthritis Rheum
25:618-623, 1982
Nifedipine treatment for Raynaud’s phenomenon
To the Editor:
We read with interest the article “Nifedipine as a
therapeutic modality for Raynaud’s phenomenon” by Winston et al ( 1 ) . We would like to report our findings with
regard to nifedipine and this condition and emphasize sevcral important results concerning the predictors of clinical
responsiveness, the dose-response relationship, the side
effects, and the efficacy of long-term therapy.
Our controlled, double-blind, randomized crossover
study of nifedipine in the treatment of Raynaud’s phenomenon (2) in 30 patients has definitely shown the effectiveness
of nifedipine on this condition. I n 2 later controlled studies,
on 17 and I5 patients with Raynaud’s phenomenon, similar
findings were reported (3,4).
Our controlled study showed that nifedipine is effective in the treatment of Raynaud’s phenomenon associated
with connective tissue diseases such as progressive systemic
sclerosis, systemic lupus etythematosus, and rheumatoid
arthritis, although it is more effective in patients with idiopathic Raynaud’s phenomenon. It remains to be seen whether these results can be explained by direerences in the
pathophysiology of Raynaud’s phenomenon (occlusive disease in the digital arteries, blood hyperviscosity, immune
complexes, and so on) (5-7) as seen in the forms associated
with connective tissue diseases.
Different doses of nifedipine have been used in 4
controlled studies: 20 mg 3 times daily in our study (2) and
the trial by Rodeheffer et al (4), 10 mg 4 times daily in the
study by Smith and McKendry (3), and 10-20 mg 4 times
daily in the study by Winston et a1 (1).
In our controlled study, 9 patients complained of side
effects (headache, flushing, nausea, and ankle edema).
At the conclusion of this study, the same 30 patients
were included in a long-term open trial. Every patient was
given nifedipine 10 mg 3 times daily, for 3 months. Raynaud’s phenomenon was associated with progressive systemic sclerosis in 9 women and 1 man (mean age 47), with
systemic lupus erythematosus in 5 women (mean age 40),
and with rheumatoid arthritis in 2 women and 1 man (mean
age 46). It was idiopathic in 10 women and 2 men (mean age
45, mean followup of disease 13.5 years).
In spite of the decrease in nifedipine dosage to 10 mg
3 times daily, 10 patients complained of headache, flushing,
nausea, and ankle edema. These side effects sometimes
disappeared with continued therapy; however, 7 patients (3
with idiopathic Raynaud’s phenomenon, 2 with progressive
systemic sclerosis, I with systemic lupus erythematosus,
and 1 with rheumatoid arthritis) discontinued the treatment
because of side effects. The results of this long-term open
study (with nifedipine 10 mg 3 times daily) were similar to
those of our controlled study (with nifedipine 20 mg 3 times
Many of our patients have now been treated with
nifedipine for more than 2 years with good therapeutic
results. We have used variable doses (10 mg 3 times daily-20
mg 4 times daily) according to the severity of Raynaud’s
phenomenon. The highest doses of nifedipine are necessary
in very severe Raynaud’s phenomenon, especially in patients with progressive systemic sclerosis and during the
winter months. Moreover, we have shown that nifedipine
may be extremely useful in the treatment of digital ulcerations in patients with progressive systemic sclerosis and
severe Raynaud’s phenomenon (8).
Our controlled study and the 3 controlled trials
published later ( 1,3,4) have demonstrated the effectiveness
of nifedipine in the treatment of Raynaud’s phenomenon. In
addition, two important conclusions must be emphasized:
that nifedipine is more effective in patients with idiopathic
Raynaud’s phenomenon than in patients with progressive
systemic sclerosis, systemic lupus erythematosus, or rheumatoid arthritis and that nifedipine is effective in the longterm treatment of Raynaud’s phenomenon, with doses of 3080 mg daily. In the majority of the cases, nifedipine was well
tolerated or side effects were so mild compared with the
improvement gained, that patients willingly accepted them.
Andre Kahan, MD
Bernard Amot, MD
Charles J. Menkes, MD
RenP Descartes University
Paris, Fmnce
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testing, men, level, androgen, arthritis, serum, results, rheumatoid, preliminary
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